Maternal L-thyroxine prevents PBDE-induced autistic-like social deficits and oxytocin depletion in mouse offspring.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with increasing prevalence, suspected to involve environmental factors. Polybrominated diphenyl ethers (PBDEs), common flame retardants, are known endocrine disruptors targeting the thyroid system. The thyroid system is crucial for brain development and regulates prosocial neuropeptides like oxytocin (OXT) and vasopressin (AVP). The specific link between PBDE-induced thyroid hormone deregulation, central OXT signaling disruption, and ASD-like social deficits has been unclear, representing a critical gap in understanding environmental neurotoxicity and potential interventions.

Researchers used C57BL6/N mice to investigate developmental PBDE exposure. Dams received daily oral doses of corn oil vehicle, 0.1 mg/kg DE-71, or 0.4 mg/kg DE-71 during gestation and lactation, with or without concurrent maternal L-thyroxine (+mT4) supplementation. Offspring were then assessed for ASD-relevant behavioral responses and central neuroendocrine OXT neuron depletion. Gene expression of Mct8, Dio3, and Esr2 in paraventricular hypothalamic (PVH) OXT neurons was also analyzed to uncover underlying molecular mechanisms.

Developmental exposure to the PBDE mixture DE-71 produced dose-dependent ASD-relevant behavioral responses and central neuroendocrine OXT neuron depletion in offspring. Molecular analysis revealed sex-specific changes in thyroid hormone-regulated pathways. In low-dose females, mRNA transcripts for the thyroid hormone transporter Mct8, deiodinase Dio3, and estrogen receptor beta Esr2 were significantly upregulated in PVH OXT neurons. Conversely, in low-dose males, Mct8 and Dio3 transcripts were downregulated. These findings highlight distinct molecular reprogramming events in hypothalamic neuroendocrine cells, leading to depleted central OXT signaling and ultimately ASD-relevant phenotypes.

Importantly, maternal L-thyroxine (+mT4) supplementation completely prevented both the ASD-relevant behavioral responses and the OXT neuron depletion caused by PBDE exposure.